The main target for a disease modifying agent for Alzheimer’s disease (AD) is amyloid beta peptide (Aβ) . Immunisation against this peptide is an interesting treatment researchers have been studying. Initial animal experiments were promising. Are we closer to any intervention with clinical benefits?
Marie Sarazin, Guillaume Dorothée, Leonardo Cruz de Souza, and Pierre Aucouturie review the present state of research in immunotherapy for AD.
First generation immunotherapy : The first anti-Aβ vaccine tested included full length Aβ42 peptide with an adjuvant that preferentially promotes T-cell-mediated immune responses .Only 20% of recipients were classified as “antibody responders.” Severe meningo encephalitis developed in 6% and trial was interrupted.The study showed that those patients with high antibody levels had less brain amyloid plaques, suggesting that antibodies cleared Aβ deposits. This clearance did not prevent neurodegeneration or improve long-term clinical course.
Second generation: These vaccines were designed for inducing strictly humoral responses to Aβ. ( to avoid the T cell mediated issues as seen with first gen). One of the Phase I studies showed that the vaccine induced the production of antibodies to Aβ in 80% of the patients without significant side effects . Assessment of its protective effect is currently underway.
Passive immunity using humanized Anti-Aβ Mono- clonal Antibodies: This can be given as IV. (trials used apineuzumab, gantenerumab, and solanezumab). Some of these reduced brain amyloid load or reduced Tau and phosphorylated-Tau levels in the cerebrospinal fluid without affecting Aβ peptide level. A large phase 3 studies, however, indicated that these antibodies failed to show a significant clinical benefit.
Intravenous immunoglobulin treatment: No symptomatic effect on cognitive and functional scales so far.
All antibodies targeted the Aβ peptide , and it is possible that this was too late to bring any benefits. General consensus is that these interventions have to be done at an earlier stage of the disease, even before the onset of clinical symptoms. Trials are suggested for cognitively normal individuals suspected to be at an asymptomatic stage of AD. Defining and Identifying the suspected individual itself is challenging. This is a heterogenous group and various associated factors need to be accounted.
Authors conclude that ‘AD is a complex puzzle and, despite numerous efforts, its relationship with the immune system remains poorly understood’. It is true that both innate and adaptive immune responses can have neuro protective effects. Fine tuning of designs and redefining of target population as well as using other strategies (new antigenic targets ( eg: tau) & methods ( e.g. enhance recruitment of monocyte-derived macrophages into the brain parenchyma) appear vital to make progress in this key area of research.
Summary of the article:
Sarazin M, Dorothée G, de Souza LC, Aucouturier P. Biol Psychiatry. 2013 Sep 1;74(5):329-32